Journal of Cancer Research & Therapy
NobleResearch
Delate T et al., J Cancer Res Ther 2014, 2(1):1-8 http://dx.doi.org/10.14312/2052-4994.2014-1
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Original research
Open Access
Factors associated with first-line bevacizumab use in advanced non-squamous, non-small cell lung cancer Delate T1,, Won K1, Carroll NM2, Kushi L3, Hornbrook M4, Bowles EJA5, Menter A6, Loggers ET5,7 and Ritzwoller D2 Pharmacy Department, Kaiser Permanente Colorado, 16601 E. Centretech Pkwy, Aurora, CO 80011, USA Institute for Health Research, Kaiser Permanente Colorado, PO Box 378066, Denver, CO 80237, USA 3 Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612, USA 4 The Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Ave, Portland, OR 97227, USA 5 Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1600, Seattle, WA 98101, USA 6 Medical Oncology Department, Colorado Permanente Medical Group, 2045 Franklin St, Denver, CO 80205, USA 7 Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA 1 2
Abstract
Introduction: Bevacizumab was approved for treatment of advanced non-squamous, non-small cell lung cancer (NSCLC) in the US in late 2006. Information on its uptake and patient and tumor factors associated with its use is lacking. Materials and methods: This was a longitudinal, retrospective cohort study of patients with stage IIIB/IV non-squamous NSCLC aged 21 years or greater diagnosed between 2005 and 2010 at four Cancer Research Network sites. Patients were categorized as receiving first-line carboplatin-paclitaxel (CP) or carboplatin-paclitaxel-bevacizumab (CPB) within 120 days of diagnosis. Information on patient and tumor characteristics was obtained from queries of sites’ electronic tumor registries and administrative databases. Factors independently associated with CPB use were evaluated using bivariate and multivariate logistic regression analyses. Results: A total of 1109 patients with advanced NSCLC were included with 198 (17.9%) and 911 (82.1%) patients receiving CPB and CP, respectively. Bevacizumab use increased modestly during the study period, peaking in 2008 at 18.5%. In bivariate analyses, patients who received CPB were younger with less comorbidity and well to moderately differentiated tumors while patients who received CP were more likely to have had hypertension, peripheral vascular disease, and a prior hospitalization. Factors independently associated with CPB use included younger age, well/ moderately differentiated tumor grade, no prior hospitalization, and more recent study year. Conclusions: Use of bevacizumab in patients with advanced NSCLC increased rapidly then moderated. Younger patients and those with lower risks for adverse effects were more likely to receive bevacizumab.
Keywords: carcinoma; non-small-cell lung; angiogenesis inhibitors; diffusion of innovation; managed care programs; health services accessibility; population characteristics
Introduction
Over the past decade, lung cancer has been the second most prevalent cancer diagnosed in males and females and resulted in the most cancer-related deaths in males aged 40 years and females aged 60 years [1-4]. In 2010, the overall prevalence of lung cancer in the U.S. was approximately 125 cases per 100,000 persons per year [5]. Non-small cell lung cancer (NSCLC) accounts for 85% to 90% of the new lung and bronchus cancer cases in the U.S. and most of these cases represent advanced disease (stage IIIB/IV) [4]. Currently, there is only a small pool of drugs that have been approved for first-line treatment of advanced or metastatic NSCLC [6]. Among these drugs is bevacizumab (Avastin). Bevacizumab is a recombinant monoclonal
antibody that originally was approved by the U.S. Food and Drug Administration (FDA) in 2004 for first-line treatment
Corresponding author: Thomas Delate, Clinical Pharmacy Research Scientist, Pharmacy Department, Kaiser Permanente Colorado 16601 E. Centretech Pkwy, Aurora, Colorado 80011, USA. Tel.: 303-739-3538; Fax: 303-739-3574; Email:
[email protected]
Received 2 October 2013 Revised 4 December 2013 Accepted 11 December 2013 Published 18 December 2013
Citation: Delate T, Won K, Carroll NM, Kushi L, Hornbrook M, Bowles EJA, Menter A, Loggers ET and Ritzwoller D (2014) Factors associated with first-line bevacizumab use in advanced non-squamous and nonsmall cell lung cancer. J Cancer Res Ther 2:1–8. doi:10.14312/20524994.2014-1 Copyright: 2014 Delate T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Delate T et al., J Cancer Res Ther 2014, 2(1):1-8
of metastatic carcinoma of the colon and rectum when used in combination with intravenous 5-fluorouracil [7]. Bevacizumab selectively binds to human vascular endothelial growth factor (VEGF), decreasing VEGF activity resulting in a reduction in tumor vascularization and decrease in tumor growth [7, 8]. In October 2006, the FDA approved bevacizumab use as first-line treatment in advanced non-squamous NSCLC when administered in combination with carboplatin and paclitaxel [7].
Although the results of the Eastern Cooperative Oncology Group (ECOG 4599) demonstrated a statistically significant improvement in survival with the addition of bevacizumab [9], it is unclear whether the 2-month survival improvement is viewed as being clinically significant by physicians in the community, particularly relative to its toxicity. Numerous clinical and biological markers can influence a patient’s candidacy for bevacizumab use (Table 1). Additionally, the clinical data that support bevacizumab’s efficacy in patients with advanced NSCLC suggest diminished efficacy in patients aged 65 years, which constitutes the majority of individuals diagnosed with NSCLC [9]. Furthermore, recent Phase I and Phase II trials have identified a promising dose/dense metronomic chemotherapy regime for NSCLC of cisplatin, oral etoposide, and bevacizumab. However while this regime showed significant antitumor activity, the incidence of adverse events (e.g., pneumonia, thromboembolism, depression) appeared to be correlated with increasing bevacizumab dose [10, 11]. Table 1 Clinical and biological markers potentially contraindicated for bevacizumab use in lung cancer patients* Marker
Small cell lung cancer
Performance status >1
Predominantly squamous cell carcinoma Tumor invasion into major blood vessels
Radiation therapy within previous 21 days
Major surgery or trauma in previous 28 days
Major surgery planned in following 28 to 42 days Uncontrolled hypertension
Major cardiovascular or cerebrovascular disease Coagulopathy
Proteinuria or renal dysfunction Hepatic dysfunction
Unhealed wound, ulcer/gastrointestinal perforation, varices, or fracture Pregnancy, lactation, or childbearing intentions Metastases within the central nervous system Recent hemoptysis
Thromboembolism
Therapeutic anticoagulation
Non-steroidal anti-inflammatory agent use/Antiplatelet use (including aspirin)
*Adapted from bevacizumab package insert [7] and Sanders et al. [9]
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Studies have examined the patient and tumor characteristics associated with bevacizumab use in colorectal cancer [12], but none have explored the characteristics of NSCLC patients who have received bevacizumab. The purpose of this study is to assess the associations of NSCLC patient and tumor characteristics and first-line bevacizumab use in community oncology. Identifying factors that may play a role when oncologists consider using bevacizumab as a treatment option for NSCLC can provide a better understanding of bevacizumab’s use in community settings and a baseline for efforts to understand evidence-based lung cancer care.
Materials and methods
Study design and setting This is a longitudinal, multi-site, retrospective cohort study. Data were obtained from four non-profit managed care organizations that are members of the Cancer Research Network (CRN) [13], including three Kaiser Permanente regions (Colorado, Northern California, and Northwest) and Group Health Cooperative (Washington). The CRN promotes collaborative cancer research in the integrated health care settings of its member institutions. The four health systems participating in this study have a combined membership of approximately six million members. The majority of cancer care was delivered by salaried physicians in plan-owned facilities at these organizations. Combined therapy of carboplatinpaclitaxel-bevacizumab (CPB) for patients with nonsquamous NSCLC was first identified at the study sites in 2005. Thus, the comparison groups include patients diagnosed with non-squamous NSCLC between 2005 and 2010 who received either first-line carboplatin-paclitaxel (CP) or CPB. Data from each study site were extracted and transferred to Kaiser Permanente Colorado for analysis. This study was approved by the Institutional Review Boards of the four participating study sites.
Patient population The study sample included patients identified from each study site’s tumor registry. Patients were 21 years of age, diagnosed with stage IIIB/IV non-squamous NSCLC between January 1, 2005 and December 31, 2010, and followed through December 31, 2011. Patients with health plan enrollment at the time of pathologically-confirmed cancer diagnosis, NSCLC as their primary cancer diagnosis, who did not receive concurrent definitive radiation and chemotherapy (i.e., administration dates of the individual modalities were within 14 days of each other), and survived at least one month after cancer diagnosis were included. Patients were followed from cancer diagnosis until death, health plan termination, or the end of the study, whichever came first. Data collection The CRN uses a federated database, the Virtual Data Warehouse (VDW), where data are stored in common data structures across study sites [13]. This model allows
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a programmer at one site to develop analytic algorithms that can be run independently at each site to extract the necessary data elements for the study. Data are derived from each health systems’ electronic medical records (EMRs) and claims databases. The VDW contains patients’ diagnoses captured with International Classification of Diseases (ICD)-9 codes, health services procedure data as captured with Healthcare Common Procedure Coding System (HCPCS) [including Current Procedural Terminology (CPT) codes] and Diagnosis-Related Group (DRG) codes, and pharmacy data that are captured with National Drug Codes (NDC). Each CRN site maintains a list of all specific NDCs ever approved for dispensing by its pharmacies. The VDW includes tumor registry data with information on each patient’s diagnosis by ICD-O code, sequence, diagnosis date, AJCC stage, tumor grade and morphology, and dates of initial cancer-related surgery, radiation therapy, and chemotherapy treatment [14]. In addition, the VDW includes information on patient demographics, hospitalizations, outpatient visits, and insurance types. Furthermore, the VDW includes a Census database. Measures of socioeconomic status (e.g., median family income) and patients’ residential addresses, which were mapped to Census block data using geocoding software, are included in the database. Death data were derived from the VDW tumor registries and membership databases, state-level death datasets, and data from the Social Security Administration.
Study outcomes The primary outcome was an analysis of the factors independently related to first-line CPB use. Eligible patients receiving first-line CP with or without bevacizumab were identified using VDW pharmacy, procedure, and infusion databases using methods described previously [15-17]. The date of the first chemotherapy treatment administration was considered the chemotherapy start date. First-line therapy was defined as all chemotherapy agents administered within eight days of the chemotherapy start date. Secondary outcomes included an assessment and comparison of patient clinical, demographic, and sociodemographic characteristics between patients who received first-line CPB vs. CP. Data analysis Patient age at the time of NSCLC diagnosis was calculated. The presence of specific comorbidities was determined using the Quan adaptation of the Charlson comorbidity index, modified to exclude cancer diagnoses [18]. The algorithm was applied to diagnoses associated with inpatient and outpatient events that occurred prior to cancer diagnosis. Patient comorbidities were identified from ICD-9 coded outpatient diagnoses prior to date of NSCLC diagnosis. Invasive surgery during the 28 days prior to the start of chemotherapy was identified from the inpatient encounter, tumor registry, and ambulatory surgery registry datasets with DRG and procedure codes.
Delate T et al., J Cancer Res Ther 2014, 2(1):1-8
Hospitalizations within six months of the NSCLC diagnosis date were identified from inpatient encounter datasets. Surrogate patient-level measures of median annual family income were obtained from VDW Census database.
All analyses were performed comparing the CPB group to the CP group. Patient characteristics were reported as means, medians, and standard deviations for interval-level variables and percentages for categorical variables. Wilcoxon rank-sum tests and chi-square tests of association or Fisher’s Exact tests (where applicable) were used to assess differences between groups for interval-level and categorical variables, respectively. To identify factors associated with receiving CPB, all factors with a p0.2 in the bivariate analyses (plus patient sex) were entered into a logistic regression model with adjustment for the clustering of practices by health plan [19]. Factors were assessed for multicolinearity. No substantial multicolinearity (i.e., rho0.3) was detected. Two-way factor interactions were constructed and tested for statistical significance. No interactions were statistically significant and, thus, none were included in the final model. All analyses were performed using SAS v9.1.3 (SAS Software Inc., Cary, NC).
Results
There were 1109 patients diagnosed with NSCLC in the participating CRN sites during the study period who were included in the analysis. A total of 198 (17.9%) and 911 (82.1%) patients received CPB and CP, respectively (Table 2). Patients were more likely to have received CPB in years 2007 - 2008 (p0.001) and 2009 - 2010 (p0.001) compared to 2005 - 2006. Patients in the CPB group were more likely to be younger (p0.001) and have a lower comorbidity index score (p0.034) than patients in the CP group. Patients in the CPB group were also more likely to have had a well or moderately differentiated tumor (p0.001). Conversely, patients in the CP group were more likely to have had diagnoses of hypertension (p0.014) and peripheral vascular disease (p0.047), and a hospitalization in the six months prior to NSCLC diagnosis date (p0.001). In the multivariate modeling with adjustment for the clustering of practices by health plan, patients aged 66 to 70 years (odds ratio (OR)0.51, 95% confidence interval (CI)0.30-0.86) and aged 70 years (OR0.44, 95% CI0.27-0.71) were associated with decreasing likelihood of receiving CPB compared to patients aged 60 years (Figure 1). In addition, patients with one or two (OR0.35, 95% CI0.17-0.754) and three or more (OR0.53, 95% CI0.3-0.83) hospitalized days in the six months prior to NSCLC diagnosis were associated with a decreased likelihood of receiving CPB compared to patients with zero hospitalized days. Converesely, patients with well or moderately differentiated tumors were associated with an increased likelihood of receiving CPB compared to patients with an unknown tumor grade (OR2.1, 95% CI1.39-3.29). In addition, patients diagnosed in years
Delate T et al., J Cancer Res Ther 2014, 2(1):1-8
Table 2 Baseline characteristics by reception of first-line bevacizumab status
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Overall cohort (n=1109)
CP + bevacizumab (n=198)
Only CP (n=911)
P-valuea
63.5 (10.1)
60.3 (10.2)
64.2 (9.9)
70 years
249 (22.5) 300 (27.1)
52 (26.3) 33 (16.7)
